Stereochemistry: Part I

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Stereochemistry Part I
Chem 313Spring Semester 2009
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Isomers and Stereochemistry

• Why Study Stereochemistry?
• Understand and appreciate the three-dimensional
  aspect of organic structures built on
  combinations of units of sp3, sp2 or
  sp-hybridized carbon atoms.
• Three dimensional aspect is
• - imprinted by structural features which are
  intrinsic to the structure
• or
• - may arise via different kinds of reactions
  involving planar (two- dimensional) substrates
• Vitally important!
• - crucial to a vast number of chemical and
  biological chemical processes e.g.
• - formation of a pair of enantiomers (mirror
  image isomers) or diastereoisomers
  (stereoisomers which are not mirror images).
• - formation of one of two possible enantiomers
• - nature and function of enzymes
• - nature and function of small biomolecules
  e.g.
• co-factors such as NAD(P)H, intracellular
  messengers etc.
• - crucial for synthesis of drugs, food
  additives, perfumes, etc.

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Isomers and Stereochemistry
Background Reading McMurry 6th Edition - Ch.
4, all sections - Ch. 6, Sections 6.5 and 6.6,
especially sequence rules and (E)- and
(Z)-stereochemical descriptors for alkenes. -
Ch.9, all sections, especially chirality and
prochiralty, and assignment of (R)- and
(S)-stereochemical descriptors to chiral
centres - Ch. 19, pages 720-721, concept of
enantiomer excess. - Ch. 25, Section 25.2
Fischer projections of carbohydrates and
relationship with D-glyceraldehyde. - Ch. 26,
Section 26.1 Fischer projections of amino
acids You must take care with descriptors
stereogenic, stereoselective and
stereospecific (textbook definitions not
accurate)
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Isomers and Stereochemistry
Stereochemistry describes spatial relationships
between constituent atoms or groups of a molecule
in two and three dimensions
Isomers (McMurry 'Organic Chemistry', Chapter
4) - Same molecular formula - Same composition
- Different 'structures' constitution or
stereochemistry
Constitutional isomers differ in 'constitution'
- different bonds or - different sequence of
bonds
Stereoisomers same constitution - sequence of
bonding is the same - differ in spatial array of
atoms or groups - may be subdivided into
'conformational' or 'configurational'.
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Constitutional Isomers
Bond region of electron density between
atoms.sometimes difficult to determine! -
bonds drawn to satisfy normal valencies of
atoms - take into account what is known about
bonded and non- bonding distances between
atoms - bonding for distance of less than 1.6 Å,
not greater than 2.7 Å (normally less than 1.6
Å).
Pauling definition chemical bond between two
atoms or groups of atoms.. leads to an aggregate
. with sufficient stability to make it
convenient for a chemist to consider it as an
independent molecular species (L. Pauling 'The
Nature of the Chemical Bond', 3rd Edition,
Cornell University Press, Ithaca, NY)
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Constitutional Isomers
Constitution - defines nature and or
sequence of bonds - constitutional isomers
differ in nature and/or sequence of bonds.
Examples
C1 C2 C1-O O-H1 etc.
C1 O C2 O etc.
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Constitutional Isomers (cont.)
Constitutional isomers may be in equilibrium!
Non-bonded distance of 2.25 Å in 1! Bond length
of 1.81 Å in 2!
2.25 Å
1.81 Å
.. .. tautomerism'
... tautomerism'
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Constitutional Isomers (cont.)
Some valence bond 'tautomers' are degenerate !
Homotropilidene -rapid Cope rearrangement gives
a 'product' identical with the 'starting
compound' degenerate structures identical!
The Cope reaction concerted pericyclic reaction
(McMurry, Ch. 30) - bond reorganization through a
chair-like transition state (McMurry, Ch. 30, p.
1149 6th edition)
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Stereoisomers
'Conformation' and 'Configuration' CHEM 111
McMurry Ch. 4 and Ch. 9 read!

• conformational isomers 'usually can't be
  isolated because
• they interconvert too rapidly at room
  temperature'
• by rotation about single bonds ..
  (McMurray, Ch. 4!)

• configurational isomers double bond isomers or
  geometric
• isomers e.g. (E)- and (Z)-2-butene cis-trans
  isomers
• (e.g. cis-and trans -1,2-dichlorocyclopropane)
• enantiomers e.g. (R)- and (S)-2-chlorobutane

'cannot be interconverted' by rotation about
bonds, by inversion at a chiral centre etc.
'at room temperature'
However problems with these definitions!
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Conformational Isomers

• Conformers differ in energy through
• torsional strain through space, repulsive
  interaction between bonding electrons in adjacent
  ?-bonds.
• ii. 'Steric strain or van der Waals strain
  through space interaction between filled orbitals
  on groups attached to adjacent atoms.
• iii. Dipolar repulsion.
• All are function of . or .. angle ?

a. ethane
sawhorse
Newman
sawhorse
Newman
..

projections
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Conformational Isomers (cont.)
Butane
Equilibrium between gauche and anti conformers
?H 0.8 kcal mol-1
gauche
anti
gauche
The anti conformer ? two gauche conformers that
are ..! - entropy change ?S - R ln2
where R (gas constant) 1.987 cal K-1 mol-1
can calculate equilibrium concentrations at 298
K ?G ?H - T?S - 0.8
kcal mol-1 - 298 (-R ln2) -
0.8 kcal mol-1 0.41 kcal mol-1
- 0.39 kcal mol-1 Therefore, as ?G
-RT ln K K 1.9 anti/gauche
Mixture consists of 66 anti, 34 gauche at 298 K
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Conformational Isomers (cont.)
Lifetimes
In general, lifetimes of individual conformers
According to rate theory k 2.084 x 1010T
e-?G/RT where R 1.987 cal K-1 mol-1 and t1/2
0.693/k for first order reaction For ?G
20 kcal. mol-1, interconversion rate 1.3 x 10-2
s-1 at 25 C half-life (t1/2) ? 60 sec For
?G 25 kcal. mol-1, interconversion rate 2.9
x 10-6 s-1 at 25 C half-life (t1/2) ? 66 hr
Note that if we express height of barrier in
terms of ?H , this has to be converted to ?G
by inclusion of entropy term. Rotational
barriers generally given by ?G (determined
experimentally by NMR spectroscopy, other
spectroscopic techniques)
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Conformational Isomers (cont.)
tetra-tert-butylethane
'anti'
120
60
? 180
'syn'
-180
'anti'
-120
-60
? 0
Barrier to rotation (?G) from 'anti' - 'syn' -
'anti' ? 22.9 kcal mol-1
slow interconversion at room temperature very
large steric or van der Waals strain!!
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Conformational Isomers (cont.)
bis-adamantyl-di-tert-butylethane
25 C
25 C
A
B
NO interconversion at room temperature very
large steric or van der Waals strain!! shows
distortion away from sp3 angle of 129 28'. The
two isomers A and B can each be isolated, and are
stable!!!!! - barrier to rotation gt 66 kcal
mol-1!!!!
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Conformational Isomers (cont.)
Dibenzobicyclo2.2.2octadienes and biaryls-
no interconversion at room temperature barrier
to rotation 36.6 kcal mol-1
25 C
A
B
very slow interconversion at room temperature
barrier to rotation 23.5 kcal mol-1 rapid
interconversion at melting point160 C!
25 C
Isomers which differ by rotation about single
bonds, and which can 'isolated' ('detected') at
'room temperature' are called 'atropisomers'
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Conformational Isomers (cont.)
no interconversion at room temperature barrier
to rotation 36.6 kcal mol-1
25 C
Common in o-substituted aromatic compounds with
large substituents
Barrier to rotation ? 27 kcal mol-1
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Conformational Isomers (cont.)
Amides and thioamides

• Barrier to rotation
• 21 kcal mol-1
• established by NMR
• spectroscopy

• Barrier to rotation
• 25.1 kcal mol-1
• isomers can be
• isolated!

In these special cases 'single bond' may have
some 'double bond' character
so called 'amide-resonance easily detected by
NMR spectroscopy
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Conformational and Configurational Isomers
Conformational Isomer or Conformer

• Definition of conformational isomers?
• 'usually can't be isolated because they
  interconvert too rapidly
• at room temperature' by rotation about
  single bonds ..
• (McMurray, Ch. 4)?

Compare with
Configurational Isomer
Definition of configurational isomers? - 'cannot
be interconverted' by rotation about bonds, by
inversion at a chiral centre etc. 'at room
temperature'
Above definitions are inadequate ?
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Configurational Isomers Reexamined
1. 'Geometric Isomers'
Consider (E)- and (Z)-2-butenes no
interconversion at room temperature!
2pz
2pz
?
20 C
?
?
Rotational barrier (? energy required to break
?-bond) ? 56.5 kcal mol-1 if temperature of
environment is ? 500 C, then interconversion
does occur!
Therefore, what happens on the surface of the
planet Venus (t ? 800 C)? - does 2-butene
behave as a conformational isomer?
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Configurational Isomers Reexamined (cont.)
Other examples and barriers to rotation
? 42.8 kcal mol-1
? 25.7 kcal mol-1
? 20.6 kcal mol-1

• 10.0 kcal mol-1 rapid rotation at room
• temperature

? 15.3 kcal mol-1
So-called 'push-pull' alkenes EDGEWG with
resonance contributor imparting 'single-bond'
character to 'double bond'
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Configurational Isomers Reexamined (cont.)
Enantiomers
S
Inversion barrier 8 kcal mol-1 at room
temperature!
Inversion barrier gtgt 80 kcal mol-1 -
..at room temperature!
R
S
R
Inversion barrier 32 kcal mol-1 at
room temperature!
R
S
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Configurational Isomers Reexamined (cont.)
cis-1,2-dimethylcyclohexane
Ring inversion barrier ? 12 kcal mol-1
Room temperature!
R
S
R
S

• . enantiomers!

Equilibrium concentration of at 25 C
is 50 of each enantiomer ? racemic mixture!
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Configurational Isomers Reexamined (cont.)
Enantiomers with no chiral carbon atoms
Rotational barrier 0.8 kcal mol-1
...at room temperature!
A
B
A and B are ..!
. at room temperature barrier to
rotation 36.6 kcal mol-1
.. at room temperature barrier to
rotation 23.5 kcal mol-1 . at
melting point 160 C!
25 C
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Configurational Isomers Reexamined (cont.)
Diastereomers
(2R,3R )- 2,3-dihydroxy- butanedioic
acid or (2R,3R)- tartaric acid
(2R,3S)- or meso- 2,3-dihydroxy- butanedioic
acid or meso-tartaric acid
m.p. 170 C
m.p. 140 C
at room temperature barrier to
inversion gtgt 80 kcal mol-1
Inversion barrier ? 8 kcal mol-1
.at room temperature!
25 C
R
R
R
S
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Configurational Isomers Reexamined (cont.)
Diastereomers (cont.)
Rotational barrier ? 1.4 kcal mol-1 rapid
interconversion at room temperature!
R
R
R
ring inversion barrier ? 12 kcal mol-1 rapid
ring inversion at room temperature!
axial
equatorial
inversion barrier ? 8 kcal mol-1 rapid
inversion at room temperature!
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Redefining Configuration and Conformation

• 1. We are chemists working on the surface of the
  planet earth! average
• laboratory temperature may be about 25 C
  ('ambient temperature')!
• Any stereoisomer which is able to be isolated at
  a designated temperature
• (usually 'ambient temperature') may be termed a
  'configurational isomer'
• - then subdivided according to geometric,
  cis-trans, diastereomer,
• atropisomer, enantiomer, etc.
• Use conformation' to describe isomers which
  differ in torsion angles
• (irrespective of the nature of the bond) about a
  designated bond or axis in
• conjunction with a further descriptor
  'enantiomer', 'diastereomer', etc.
• providing that the isomers undergo rapid
  interchange at the designated
• temperature (usually 'ambient temperature').

Isolation criterion measurable lifetime (usually
t1/2 1000 sec) at 298 K, ?G ? approx. 22 kcal.
mol-1.
Note that the clear and unambiguous distinction
between 'configurational' and 'conformational' is
difficult, and the matter is still under debate!
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Redefining Configuration and Conformation (cont.)
Examples
. at 25 C ?G ? 0.8 kcal
mol-1
.. - at 25 C ?G gt 66 kcal
mol-1
. at 25 C ?G ? 12 kcal
mol-1
. at 25 C ?G ? 12 kcal
mol-1
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Redefining Configuration and Conformation (cont.)
.. at 25 C ?G ? 23.5 kcal
mol-1
.. - at 25 C ?G ? 25.1 kcal
mol-1
.. at 25 C ?G ? 8 kcal
mol-1.
at 25 C ?G ? 32 kcal mol-1.
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Redefining Configuration and Conformation (cont.)
.. at 25 C ?G ? 8
kcal mol-1
Residual stereoisomerism subset of total set of
stereoisomers that can be distinguished under a
specified set of conditions by a given technique
(R)-2-Chlorobutane large number of
conformations, but chiral centre at C2 is the
only stereochemical feature observable at 25 C
(by NMR spectroscopy in a chiral solvent) this
is the 'residual stereoisomerism'.